1. Field of the Invention
Morphine is a well known narcotic analgesic having the structural formula: ##STR1##
The compound of this invention is structurally related to morphine and is named according to the morphinan system of nomenclature using the morphinan nucleus which is shown below: ##STR2## The numbering and stereochemical placement of atoms in the morphinan system is the same as that depicted for morphine. A dashed line is used to represent a covalent bond projecting below the plane of a reference atom while a wedged or heavily accented line signifies a covalent bond above such plane. The compound of this invention has the same stereochemical placement of atoms as depicted for morphine.
Morphine and its structurally related relatives are used primarily as analgesics. While extremely effective for the relief of moderate to severe pain these compounds are narcotic and most possess dependence-inducing ability and produce other side effects such as emesis, constipation, sweating, respiratory depression and myosis which make them less than ideal analgesics. It is impossible to predict, based on structure alone, whether a particular morphine-like compound will act as an analgesic (agonist), a narcotic antagonist or possess a combination of these properties since very minute structural modifications in the molecule can significantly change the way it affects an individual to which it is administered. A compound with the appropriate profile of analgesic (agonist) and narcotic antagonist actions has potential for treatment of moderate to severe pain without the liability of drug dependence or drug abuse. The compound of the present invention is a potent mixed analgesic/narcotic antagonist with an acceptable ratio of analgesic activity to narcotic antagonist activity.
2. Prior Art
Morphinans which are hydroxy substituted in the 14-position are known. Thus, I. J. Pachter reports in Narcotic Antagonists, Advances in Biochemical Psychopharmacology, Vol. 8, Raven Press, New York 1973, p. 57, the preparation of compounds having the structure: ##STR3## where R is cyclopropyl (A) or cyclobutyl (B). The compound in which R is cyclopropyl is reported to be essentially a narcotic antagonist while that compound in which R is cyclobutyl is reported to possess both analgesic and narcotic antagonist activity. This article also reports the preparation by the Shionogi Company in Japan of a compound having the formula: ##STR4## It is stated that this compound is very long acting and more potent than (A) (above), cyclazocine or naloxone. Naloxone is a potent narcotic antagonist whereas cyclazocine has mixed analgesic/narcotic antagonist activity. This compound was found to have analgesic activity (designated as ED.sub.50) of 2.2 mg./kg. and narcotic antagonist activity (designated as AD.sub.50) of 0.082 mg./kg.
Compounds of the general formula: ##STR5## where R is a hydrogen atom or hydroxyl group; R.sub.1 is allyl, .gamma.,.gamma.-dimethylallyl or cyclopropylmethyl; and F represents the presence or absence of a double bond are disclosed in U.S. Pat. No. 3,654,280 which issued Apr. 4, 1972.
A compound of the formula: ##STR6## is disclosed in European Patent Bulletin number 1980/24 under the publication number 0019254. The compound is described as having analgesic activity of 9.87 mg./kg. and narcotic antagonist activity of 5.2 mg./kg.